Long-term follow-up of 37 patients with refractory partial seizures treated with vagus nerve stimulation

] Epilepsy 1993;6:206-214 © 1993 Butterworth-Heinemann

Long-Term Follow-Up of 37 Patients with Refractory Partial Seizures Treated with Vagus Nerve Stimulation Lori K. Holder, J. F. Wernicke, and W. Brent Tarver

Stimulation of the vagus nerve for the treatment of refractory seizures of partial onset has been studied in two pilot studies and one randomized, blinded, parallel study. Results from the controlled study have been promising, but more information is required regarding the long-term safety and efficacy of vagus nerve stimulation. A cohort of the first 37 patients to finish the controlled study was examined on a long-term basis. The response of patients at I year and 18 months of stimulation revealed that efficacy does not decrease over time. The system is well-tolerated, and no major adverse events occurred with long-term exposure to the stimulation. Normal device end of service occurred in a majority of the patients, with most choosing to have their generators replaced. This analysis demonstrates that stimulation of the vagus nerve for the treatment of refractory epilepsy manifested by seizures of partial onset continues to be safe and effective over extended periods of time. Key Words: Vagus nerve--Nerve stimulation--Epilepsy-Long-term follow-up.

Vagus nerve st~'nulation (VNS) for the treatment of refractory seizures with partial onset has been studied in clinical trials (1-10). To date, two pilot studies (E01 and E02) and one randomized, blinded, parallel study (E03) have been conducted using the NeuroCybernetic Prosthesis (NCP) System to stimulate the vagus nerve. The pilot studies indicated that use of the system for the treatment of partial seizures appears to be safe and effective in patients with refractory seizures of partial onset (1-7). A randomized, blinded, parallel study was conducted to conclusively demonstrate the safety and efficacy of VNS in a larger patient population (8-10). Although results of the controlled study are promising, the issue of long-term safety and efficacy has not been addressed. This article discusses

Received March 17, 1993; accepted April 15, 1993. From Cyberonics, Inc., Webster, TX, U.S.A. Address correspondence and reprint requests to L IC Holder at Cyberordcs, Inc., 17448 Highway 3, Suite 100, Webster, TX 77598-4135, U.S.A. 206

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extension data for the first 37 patients to complete the randomized portion of the E03 study (7).

History Although the history of the use of VNS for the treatment of seizures has been addressed in other sources, the results of the h u m a n studies are briefly reviewed here. Two h u m a n pilot studies (E01 and E02) have been conducted with a total of 15 patients at three investigational sites. For both studies combined, the mean percent change in seizures p e r day from control was - 4 2 . 8 % with a median change of - 4 2 . 0 % (mean exposure to stimulation = 22.1 months; median = 21.6 months) (8). Analysis of the first 37 patients to complete the randomized, blinded, parallel study (E03) has demonstrated similar efficacy (8). After 3 months of stimulation, a statistically significant difference in seizure rates from baseline to stimulation (p = 0.025) was seen between the two randomization groups. Patients receiving optimal stimulation para-

LONG-TERM VAGUSNERVE STIMUI~TION

meters experienced a mean decrease in seizures per day of 33.3% from the baseline period (p < 0.001). Patients receiving less or noneffective stimulation parameters experienced a mean reduction in seizures per day of 8.3% from the baseline period (p -- 0.2). In all studies, hoarseness and voice change are the only adverse events cited a significant number of times by patients (1-10). Serious adverse events were experienced by 2 of the 129 patients who participated in the 3 studies. During the pilot studies, 1 patient experienced partial vocal cord paralysis after implantation of the system but before activation of stimulation. This occurred as a result of the surgical technique. Once the system was removed, the patient's vocal cord function recovered completely. The implantation technique has been revised to prevent such complications (11,12). In the randomized study, one patient experienced a generator short circuit that resulted in direct current being applied to the nerve for several hours. The generator was removed and replaced, but the new generator has not been activated. As of the patient's last ear, nose, and throat examination, the left vocal cord is completely paralyzed with compensation from the right vocal cord (8). Recently, the patient reported that her voice has returned t o normal.

Methods

VNS System

VNS was delivered via the NCP System (13). The implantable portion of the NCP System consists of the NCP Generator and the Bipolar Vagus Stimulation Lead. The implant configuration is shown in Fig. 1. A tunneling tool to aid in placement of the lead during surgery is also available. Peripheral components of the system include the NCP Programming Wand and NCP Programming Software. The generator is programmed externally using the programming wand and the NCP Software installed on any IBM or IBMcompatible personal computer. Once programmed, the NCP Generator stimulates intermittently at programmed settings until it is reprogrammed. The NCP Generator can also be manually activated with a magnet by the patient or a companion. The parameters delivered with magnetic activation do not have to be the same as the intermittent stimulation. In the case of intolerable stimulation or device malfunction, the magnet can be taped over the generator to inhibit its output.

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Study Design

The E03 study was a blinded, prospectively randomized, parallel study. The study design has been discussed in previous publications (8-10) but is shown in Fig. 2 for review. All patients enrolled in this study had medically refractory partial seizures and met required inclusion and exdusion criteria. Patients were randomly divided into two groups, those receiving high (optimal) stimulation, and those receiving low (less or noneffective) stimulation. After completion of a 14-week controlled period, patients entered an extension phase during which the individual's generator could be programmed to parameters the investigator deemed appropriate (all patients received high parameters). Patients were followed according to the investigator's schedule but were required to be examined at least once every 3 months. If at any time the patient and investigator believed that the treatment was not benefidal, they could stop stimulation and, if desired, have the device explanted. All patients enrolled in the study continued taking anticonvulsant drugs. Alterations in drugs and dosages were discouraged during the controlled portion of the study but were permitted during the extension phase. Efficacy

The primary parameter for the determination of efficacy for this study is seizure frequency expressed in seizures per day. All analyses are based on a comparison between the seizures per day recorded dur208 ] EPILEPSY, VOL. 6, NO. 4, 1993

ing the baseline and stimulation periods and are expressed as the percent change in seizures per day from baseline. A comparison of the response between patients assigned to each of the two randomization groups was performed. In addition, the response of patients achieving I year and 18 months of stimulation is discussed. It is important to note that the analysis included all periods during which the patient received stimulation. Periods of less-effective stimulation for patients randomized into the low group during the controlled study were not excluded. Statistical Methods

This analysis employed standard statistical methods, and all calculations were performed using the Statistical Analysis System (SAS) (14). Student's t test was used most frequently during the analysis. The null hypothesis is based on a hypothetical change of zero between the baseline and stimulation periods. For a p value < 0.05, the null hypothesis is rejected and a statistical difference is detected. The Wilcoxon ranksum test was used to confirm the results of Student's t test.

Results Investigation Sites and Patient Population

The E03 study was conducted at 17 sites (12 in the United States) and enrolled a total of 125 patients. Eleven patients discontinued participation in the study before implantation of the device. Two patients discontinued after implantation; one before activation due to guardianship issues and one after activation due to the generator malfunction (short circuit). The NCP System is still imp!anted in both patients. The first patient now receives stimulation but was not randomized for humanitarian purposes. The second patient has not opted to continue treatment at this time but may do so in the future. For this analysis, only extension data from the first 37 patients to complete the controlled portion of the study are examined. Of these 37 patients, none have died or been lost to follow-up. Baseline characteristics of the group are summarized here for reference. The mean age of the patients was 33.9 years with an average of 20.8 years of epilepsy. The mean number of seizures per day recorded during the baseline period was 1.5 with a median of 0.8. All of the patients reported having partial seizures with most reporting complex partial seizures.

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Seizure Frequency Seizure records from each patient were recorded at every visit, then the seizures were divided into 3month (90-day) intervals for analysis. The first 90 days consist of the stimulation period during the controlled study. Only complete 90-day blocks are included; partial periods are excluded from the analysis. The average exposure to stimulation was 15.6 months (range, 9-18 months). The response of individual patients for each randomization group for the last 3-month period as compared.to baseline is seen in Fig. 3. The pattern of patient response between the two groups is very similar. In both groups, some patients did very well with treatment, whereas other patients had little or no change in seizure frequency. Patients originally in the low group who received high parameters in the extension phase experienced a mean change in seizures of -45.47% between the last 90-day block and baseline (average period of 15.7 months of stimulation) with a median change of -42.5%. Patients originally in the high randomization group who continued at these parameters had a mean change in seizures of -33.7% between the last 90-day period and baseline (average period of 15.3 months of stimulation) with a median change of - 44.2%. The discrepancy between the two means can be attributed to patient K03 in the high group with a mean change of 117% from baseline. This patient had 0.23 seizures per day at baseline and 0.5 seizures per day during the last period. The reason for the increase in this patient's seizures in not known. Figure 4 demonstrates the mean percent change in

seizure frequency by visit for each randomization group starting with the controlled portion of the study (months 1-3). Although both groups respond to stimulation, it is interesting to note that the response pattern is not identical between the two groups. The high group tends toward a large decrease in the period immediately after beginning stimulation, whereas the low group, receiving nonoptimal parameters during the first period, shows a tendency toward gradual reduction in seizures, with the mean seizure reduction becoming virtually identical to that experienced by the high group by the fifth stimulation period (months 13-15). The reason for the lag between the response to optimal stimulation between the two groups is not known, but it is hypothesized that initial treatment with less-effective stimulation may somehow delay the effect of future therapy with optimal stimulation. The question often arises as to whether the patient accommodates to stimulation and if the initial pattern of seizure reduction is maintained. Figures 5 and 6 show mean and median percent change in seizures per day from baseline for cohorts of patients who have received 1 year and 18 months of stimulation, respectively. Figures 7 and 8 show the mean and median seizures per day recorded for each 90-day interval for the same cohorts of patients. Although the response pattern fluctuates (as do normal seizure patterns), the relatively consistent reduction in seizures indicates that effectiveness of the stimulation does not decrease over time. Table I compares the p values (stimulation vs. baseline) for a pool of all 37 patients, patients receiving I year of stimulation, and ] F_,PILF_.PSY,VOL. 6, NO. 4, 1993

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patients receiving 18 months of stimulation. As indicated in Table 1, Student's t test reveals continued statistical significance for all visits in each of the patient pools. As mentioned before, patients continued taking their anticonvulsant medications. Since a change in dosage could alter (increase or decrease) the patients' seizure rates, the dosage levels recorded during the extension phase were evaluated for any changes. No significant increase or decrease in anticonvulsant drug dosages were noted during the extension phase.

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Device Replacements The generator initially implanted in the 37 patients had an expected battery life of 18 months. Since many of the patients have had their NCP System implanted for this length of time or longer, it is expected that the majority should have experienced a generator end of service (EOS). Of the 37 patients in this analysis, 29

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imM-° have experienced a generator EOS; the generators of the other eight patients are still functional. Sixteen of the 29 patients have subsequently had their generators replaced. A total of 13 patients have not had their generators replaced. Two of the 13 are currently pursuing other forms of treatment before opting for replacement of the pulse generator. One of the two is participating in an investigational drug trial. If the drug is unsuccessful, the patient plans to replace the generator. The second has opted to seek another form of medical therapy but has not decided to formally discontinue the study or have the device explanted.

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Device Complications Device complications occurring during the extension phase of the study can be attributed to the NCP Generator and NCP Lead. One generator could not be communicated with during programming; after device reset no further problems were encountered. One patient first experienced stimulation that did not seem as strong as before, then felt erratic stimulation and a painful pulse. This patient's generator was replaced. At a later date, this same patient experienced erratic stimulation and complained that the magnet did not stop stimulation. After resetting the device,

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the patient reported no further problems. The generator of one patient "locked up" when programming was attempted and had to be reset. Upon investigation into the anomaly, it was discovered that if a seldom-used parameter was changed, a device lockup would occur. The extended life generator does not allow the option of changing this parameter. Several complications can be attributed to the NCP Lead and its performance over time. After 1 year of stimulation, investigators were requested to perform x-rays of the NCP Generators and Leads in all of their patients to verify lead integrity. Lead impedances

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212 ] E,PILEPSY, VOL. 6, NO. 4, 1993

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were measured at the initial implant and again at the replacement surgery for comparison. On average, impedances measured at replacement demonstrated a 25-30% increase over those measured at the original implant. At their replacement surgery, four patients had impedances that were noticeably higher in one lead than the other. As a result, their systems were unipolarized during replacement surgery. One patient had a broken lead, which was confirmed by x-ray and impedance measurements taken during surgery. The broken lead was removed and replaced with a new lead. One patient's lead was accidentally cut during surgery to replace the NCP Generator. This patient subsequently had his lead unipolarized to correct the discontinuity. Similar complications and corrective measures have been discussed previously (15).

safety Routine A d v e r s e Events

Adverse events were reported by the patients at each visit and are included without presumption of causality. Several patients experienced coughing and a choking sensation while having their NCP Generator programmed to new parameters. These symptoms disappeared when stimulation levels were decreased. During the controlled portion of the study, hoarseness during stimulation was the only event reported significantly more often during stimulation than at baseline. As shown in Fig. 9, hoarseness

during stimulation continued to be reported by approximately 5% of the patients through Visit 11. Although the analysis follows through Visit 18, the reports diminish after Visit 11, and no reports of hoarseness were recorded after Visit 13. The exact reason for this is not known but may be either accommodation of the nerve to the stimulation or possibly relaxed reporting during the extension phase of the study. Although other adverse eventswere recorded during the extended phase, less than 5% of the patients reported them at any one visit. Discontinuations

Several patients have decided to formally discontinue VNS. Discontinuation does not preclude the patient receiving treatment at a later date. In all cases, the decision to discontinue and the evaluation of whether or not the treatment was beneficial was made by the patient and his physician. Of the 37 E03 study patients discussed here, 7 (20%) have opted to discontinue treatment during the extension phase of the study. The reason given for discontinuation of treatment for each of these patients is lack of efficacy. Three of the seven patients decided to discontinue after experiencing device EOS. They have opted to wait for explant in case they change their minds about discontinuation. The other four patients chose to have stimulation turned off before device EOS. One of the four patients had the device explanted, whereas three of the four opted to wait for explant in case they change their minds about discontinuation. A formal notice of discontinuation has been received from each patient's physician. ] F_~ILF,PSY, VOL. 6, NO. 4, 1993

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Discussion The purpose of collecting and evaluating extension data from the first 37 patients to complete the randomized, blinded, parallel study is to establish that stimulation of the vagus nerve continues to be safe and efficacious over time. Analysis of the data demonstrates that the majority of patients receive a beneficial effect from optimal (high) stimulation parameters, and this effect is not reduced with time. In fact, efficacy improves with time. A statistically significant reduction in seizures between baseline and all stimulation periods was demonstrated for the mean of the all-patient cohort. After beginning treatment with optimal parameters, patients who were previously randomized into the low treatment group demonstrated a treatment response similar to that of patients who started in the high group and continued with these parameters. Initial response for patients originally in the low group seems to lag behind that of patients in the high group, but, after extended periods of stimulation, the two groups show similar mean responses. Patients receiving I year and 18 months of stimulation, regardless of which paradigm they initially received, continue to respond well to the treatment with no signs of accommodation. Normal battery depletion has occurred in a majority of the patients. Most have had to plan to have their generators replaced with an extended life generator. The NCP Systems in four patients have been unipolarized during generator replacement surgery due to high lead impedance in one lead. The lead of another patient was unipolarized after the surgeon accidentally severed one of the leads during replacement surgery. One patient's lead was replaced due to high impedance in both leads measured at the time of replacement surgery, suggesting a b r o k e n lead. Complications attributed to the NCP Generator have b e e n corrected by resetting or reprogramming the device. Stimulation continues to be well-tolerated with few unanticipated adverse events. As reported previously, hoarseness during stimulation is the only event reported a significant n u m b e r of times during both the controlled and extension portions of the study. Seven patients have opted to discontinue treatment with the NCP System during the extension phase. The reason for all of the discontinuations has been a lack of efficacy. Use of vagus nerve stimulation for the treatment of seizures of partial onset shows promising results. Long-term data collected for 37 patients involved in a randomized, blinded, parallel study demonstrates 214 ] EPILEPSY, VOL. 6, NO. 4, 1993

that there is no loss of efficacy over time and that some patients continue to experience a reduction in seizure frequency with continued exposure. Long-term safety and efficacy data are continuously being collected for all of the patients enrolled in the E03 study. Data for the entire patient population will be reported in the future.

References 1. Uthman BM, Wilder BJ, Ramsay RE, Tarver WB, Wernicke JF. Treatment of epilepsy by stimulation of the vagus nerve (abstr 274P}. Neurology 1991;41 (Suppl 3): 195. 2. Penry JK, Dean JC. Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia 1990;31(Suppl 2):$403. 3. Uthman BM, Wilder BJ, Hammond EJ, Reid SA. Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 1990;31(Suppl 2) :$44-50. 4. Wilder BJ, Uthman BM, Hammond EJ. Vagal stimulation for control of complex partial seizures in medically refractory epileptic patients. PACE 1991;14:108-15. 5. Penry JK, Dean JC, Bell W, Graves S. Vagal nerve stimulation for seizure control: long-term observation. Epilepsia 1991;32(Suppl 3):59-60. 6. Uthman B, Wilder BJ, Hammond EJ, et al. Safety and tolerability of vagal stimulation. Epilepsia 1991;32 (Suppl 3):90. 7. Uthman BM, Ramsay RE, Wilder BJ, Hammond EJ. Two-year follow-up of pilot study patients receiving vagal stimulation for partial epilepsy (abstr). Epilepsia 1992;33 (Suppl 3): 102. 8. Holder LK, Wernicke JF, Tarver WB. Treatment of refractory partial seizures: preliminary results of a controlled study. PACE 1992;15:1557-71. 9. Salinsky M, Sonnen A, Kuzniecky R (NCP Study Group). Refractory epilepsy treated with vagal stimulation in a randomized parallel study: acute phase (abstr). Epilepsia 1992;33 (Suppl 3): 102. 10. Ramsay E, Ben-Menachem E, Upton A, Ristanovic R (NCP Study Group). One-year follow-up of 29 patients with refractory epilepsy treated in a controlled study of vagal stimulation (abstr). Epilepsia 1992;33 (Suppl 3): 102. 11. Reid SA. Surgical technique for implantation of the neurocybernetic prosthesis. Epilepsia 1990;31(Suppl 2) :$38-9. 12. Landy HJ, Ramsay RE, Slater ], Casiano RR, Morgan R. Vagus nerve stimulation for complex partial seizures: surgical technique, safety, and efficacy. J Neurosurg 1993;78:26-31. 13. Terry RS, Tarver WB, Zabara ]. An implantable neurocybernetic prosthesis system. Epilepsia 1990;31 (Suppl 2) :$33-7. 14. SAS Institute, Inc. SAS/STAT User's Guide, Release 6.03 ed. Cary, NC: SAS Institute, Inc., I988:1028 pp. 15. Tarver WB, George RE, Maschino SE, Holder LK, Wernicke JF. Clinical experience with a helical bipolar stimulating lead. PACE 1992;15:1545-56.